A .beta.-bend is a reversal in the direction of the backbone chain of a peptide, as a result of which the peptide becomes folded and more compact, and assumes a more stable conformation. Further, since the binding portions of the peptide are held in proper orientation for receptor interaction, a neuropeptide including a .beta.-bend typically serves as a better ligand for a receptor site. Some neuropeptides, such as the cyclic peptides oxytocin, somatostatin and vasopressin, exist naturally in predominantly bent forms. Linear neuropeptides, which are flexible can assume a variety of conformations, including a .beta.-bend, typically as a result of hydrogen bonding or solvent interaction. Such bonds are weak, however, and to the extent that they are destroyed, the biological activity of the peptide is diminished.
Previous attempts to introduce a conformational restriction in linear peptides involved replacing certain amino acid residues with other amino acids containing bulkier side chains, which limit the rotational space accessible about the backbone, and cyclizing the peptides, forcing them into a folded structure. These approaches share some undesirable characteristics. First, the introduction of the bulky groups of the added functionalities necessary to bend the peptide offer the possibility that these groups will interfere with the interaction with the receptor, even though they may promote the proper backbone conformation. Secondly, these analogs are far from rigid, and, even though their conformational space is somewhat restricted, these compounds can assume a variety of conformational states in addition to the desired .beta.-bend.
An analog of methionine enkephalin incorporating an intermediate perhydronaphthalene moiety in the backbone chain for maintaining a permanent .beta.-bend is known (Belanger et al., Can. J. Chem. 60, 1019-1029, 1982). The perhydronaphthalene derivative, however, was found to have only weak biological activity.